Gaucher Disease
Gaucher disease is a lysosomal storage disorder that is associated with the accumulation of glycosphingolipids (GSL) in cells, particularly monocytes and macrophages, of afflicted individuals. This aberrant build up of GSL results from a genetic deficiency (mutation) in the lysosomal enzyme acid β-glucosidase (GCase; glucocerebrosidase), the lysosomal hydrolase that breaks down the GSL glucosylceramide (GluCer). The majority of Gba mutations cause GCase protein to misfold in the endoplasmic reticulum (ER). Misfolded GCase is recognized by the ER quality control system and subsequently degraded instead of being processed and trafficking to the lysosome (Street et al., Proc Natl Acad Sci USA 2006; vol. 103; no. 37: 13813-18).
Gaucher disease is pan-ethnic, with an overall disease frequency of about 1 in 50,000-100,000 births. Certain populations have a higher prevalence of Gaucher disease. In the Ashkenazi Jewish population, for example, about 1 in 15 people are carriers for a Gba mutation (Aharon-Peretz et al., New Eng. J. Med. 2004; 351: 1972-77). According to the National Gaucher Foundation, about 2,500 Americans suffer from Gaucher disease.
Gaucher disease is an autosomal recessive disorder and is the most common lysosomal storage disease. The disease has been classified into three clinical types, depending on neurological involvement and disease severity (Cox et al., Q J Med. 2001; 94: 399-402). Type 1 is the most common and is characterized by an absence of neurological involvement. Type 1 patients exhibit a broad spectrum of severity, and some can remain asymptomatic throughout life. Most Type 1 patients exhibit enlargement of the spleen and liver, skeletal abnormalities and bone lesions, and sustained inflammatory reactions. Hepatic glucocerebroside levels are elevated from 23-fold to 389-fold above normal levels in Type I Gaucher patients.
Type 2 Gaucher disease is the rarest, most severe form, and is associated with early onset of acute neurologic disease. The characteristic feature of neuronopathic Gaucher disease is an abnormality of horizontal gaze. Afflicted patients develop progressive encephalopathy and extrapyrimidal symptoms such as rigidity and Parkinson's-like movement (parkinsonism). Most Type 2 Gaucher patients die in early childhood from apnea or aspiration due to neurological deterioration.
Type 3 Gaucher disease also has neurological involvement, although to a lesser extent than Type 2. Type 3 patients also have the hepatosplenomegaly and skeletal defects characteristic of Type 1, and central nervous system symptoms that include poor coordination of movements (ataxia), seizures, paralysis of the eye muscles, epilepsy, and dementia. People with Type 3 Gaucher disease can live into adulthood, but may have a shortened life span. Three sub-classifications of Type 3 have been reported: Type 3a, which is associated with prominent hepatosplenomegaly and bone marrow disease; Type 3b, which is associated with limited systemic symptoms; and Type 3c, which is associated with hepatosplenomegaly, corneal opacities, progressive ataxia and dementia, and cardiac valve and aortic root calcification.
Over 200 Gba mutations have been identified in affected Gaucher patients. Most Gaucher patients exhibit some residual GCase activity. However, a poor correlation of genotype with phenotype has plagued efforts to elucidate the molecular basis for phenotypic variation (Sidransky, Mol. Genetics and Metab. 2004; 83: 6-15). There is a lack of phenotypic consistency even among identical twins harboring the same genetic mutations. Despite this, different mutations are associated with the three disease types. The presence of point mutation N370S on at least one allele (heterozygotes) is almost universally associated with type 1 Gaucher disease (Cox, supra).
Treatment
Treatment of clinically manifested Types 1 and 3 disease is predominantly by enzyme replacement therapy (ERT) of recombinant GCase (Ceredase® and Cerezyme®, Genzyme Inc.). Bone marrow transplants (BMT) also have been employed as treatment for Gaucher disease (Types 1 and 3). Because macrophages are derived from bone marrow stem cells, allogeneic bone marrow transplantation (BMT) has been applied successfully in a small number of Gaucher patients. However, BMT can be associated with severe morbidity and mortality, and only a small fraction of patients have appropriate histocompatible donors.
A third, relatively recent approach to treating protein deficiencies involves the use of small molecule inhibitors to inhibit synthesis the natural substrate of the deficient enzyme protein, thereby ameliorating the pathology. This “substrate reduction” approach (SRT) has been specifically described for a class of about 40 related enzyme disorders called lysosomal storage disorders or glycosphingolipid storage disorders including Gaucher disease.
A fourth approach, a specific chaperone strategy, rescues mutated proteins from degradation presumably in the endoplasmic reticulum (ER) or in other cellular protein degradation/disposal systems. In particular embodiments, this strategy employs small molecule reversible inhibitors which specifically bind to a defective lysosomal enzyme associated with a particular lysosomal disorder. In the absence of therapy, the mutated enzyme folds improperly in the ER (Ishii et al., Biochem. Biophys. Res. Comm. 1996; 220: 812-815), is retarded in its maturation to a final product, and is subsequently degraded via ER associated degradation pathways. The chaperone strategy involves the use of a compound that facilitates the correct folding of a mutated protein, to prevent undue or abnormal degradation from the ER quality control system, or accumulation of misfolded protein in the cell. These specific chaperones are designated specific pharmacological chaperones (or active site-specific chaperones).
The chaperone strategy has been described and exemplified for enzymes involved in lysosomal storage disorders as in U.S. Pat. Nos. 6,274,597, 6,583,158, 6,589,964, 6,599,919, and 7,141,582, to Fan et al., which are incorporated herein by reference in their entirety. Rescue of GCase from Gaucher patient cells has been described using the imino sugar, isofagomine (IFG), and its derivatives, and using other compounds specific for GCase (described in pending U.S. patent application Ser. Nos. 10/988,428, and 10/988,427, both filed Nov. 12, 2004). Such compounds include glucoimidazole ((5R,6R,7S,8S)-5-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyridine-6,7,8-triol).
Surrogate Markers
Despite the phenotypic inconsistency, Gaucher patients exhibit several consistent surrogate markers of the disease that are used to evaluate clinical response to treatment. The present invention relates to a method of monitoring treatment of a Gaucher patient following treatment with a specific pharmacological chaperone, by evaluating changes in at least one, and preferably multiple, surrogate markers of Gaucher disease.